ORIGINAL ARTICLE Copyright © 2010 Via Medica ISSN 1897–5593
Address for correspondence: Magdalena Kosydar-Piechna, MD, Department of Cardiac Rehabilitation and Noninvasive Electrocardiology, Institute of Cardiology, Alpejska 42, 04–628 Warszawa, Poland, tel: +48 22 343 44 08, fax: +48 22 343 45 19, e-mail: mkosydar@ikard.pl
Received: 5.11.2009 Accepted: 12.03.2010
Influence of exercise training on leptin levels in patients with stable coronary artery disease: A pilot study
Magdalena Kosydar-Piechna1, Maria Bilińska1, Jadwiga Janas2, Ryszard Piotrowicz1
1Department of Cardiac Rehabilitation and Noninvasive Electrocardiology, Institute of Cardiology, Warsaw, Poland
2Department of Clinical Biochemistry, Institute of Cardiology, Warsaw, Poland
Abstract
Background: This study was designed to examine the influence of exercise training on leptin levels in patients with stable coronary artery disease (CAD).
Methods: Sixty-four male patients, mean age 55.6 ± 6.0 years, were randomized either to six weeks of aerobic training, three times a week, at 60–80% of maximal heart rate (training group, Ex, n = 32) or to a control group (n = 32). Exercise stress test was performed and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference and plasma leptin levels were measured at the beginning and end of the study.
Results: Physical capacity increased significantly only in Ex patients (max workload in METs from 7.7 ± 1.4 to 8.2 ± 1.4, p < 0.05). There were no significant differences between initial and final results in either group in terms of BMI, WHR or waist circumference.
Although, at the end of the study, leptin levels did not change in Ex patients (6.7 ± 3.2 vs 6.9 ± 3.6 ng/mL, NS), they did increase significantly in the control group (8.0 ± 4.0 vs 9.3 ±
± 5.2 ng/mL, p < 0.02).
Conclusions: A short period of exercise training in CAD patients improved their physical capacity, but did not influence BMI, WHR and waist circumference. Exercise training pre- vented an increase in leptin levels during the study period. (Cardiol J 2010; 17, 5: 477–481) Key words: coronary artery disease, exercise training, leptin levels
Introduction
Adipose tissue, as an active endocrine organ, releases proteins termed adipokines, including a hor- mone known as leptin. It has been established that increased leptin levels are common in obese and dia- betic patients and independently associated with in- sulin resistance [1], cardiovascular diseases [2, 3], and low-grade chronic inflammation in humans [4, 5].
To date, the influence of regular physical ac- tivity on leptin levels has been examined in healthy subjects as well as in obese and diabetic patients.
The effects of exercise training on leptin le- vels in patients with coronary artery disease (CAD) are unknown. Therefore, the aim of this pilot study was to assess the influence of six- weeks of exer- cise training on leptin levels in patients with stable coronary artery disease.
Methods
We enrolled consecutive male patients < 65 ye- ars, with stable CAD, who had been referred for our exercise training program between 1 January and 31 December 2007. We excluded patients with heart failure, unstable angina, diabetes mellitus, un- controlled arrhythmias, poorly controlled hyperten- sion, hemodynamically significant valvular heart disease, those with chronic inflammatory, autoim- mune, neoplastic, or other systemic diseases, chronic hepatic or kidney diseases. All the patients were clinically stable at least one month before their inclusion in the program, without any changes in medical treatment. The subjects received standard medications such as statin, aspirin, beta-blocker and angiotensin-converting enzyme inhibitor. The dos- es of medications were not changed during the study period. The study protocol was approved by the Local Ethics Committee. Afterwards, a written informed consent was obtained from each patient.
The patients were randomized into two groups:
training group (Ex) and control group. Ex patients agreed to participate in our training program. The baseline evaluation included clinical history and examination, resting electrocardiogram, chest X-ray, two-dimensional echocardiogram, blood chemistry (total and high- and low-density lipopro- tein cholesterol, triglycerides, fasting and post- prandial glucose levels, and liver and kidney func- tion tests), We defined patients as non-smokers when they had not smoked tobacco for at least one year. All the patients were advised to follow a diet containing limited amounts of fat and high-carbo- hydrate foods, and not to change the diet during the study protocol.
Anthropometry
Fasting body weight and height were measured (B 150 L, Axis, Poland) in all participants wearing only underclothes, without shoes. Height was mea- sured without shoes to within an accuracy of 1 cm.
Waist-to-hip ratio (WHR) was measured as a ratio of the circumference of the waist [cm] to that of the hips [cm]. Body mass index (BMI) was calculated as [kg/m²].
Blood sampling and laboratory measurements
All the participants were told to avoid vigor- ous exercise for four days before blood sampling.
Blood samples were collected between 8 and 10am
after an overnight fast. EDTA was added to whole blood for plasma preparation. The parameters of blood chemistry e.g. glucose, lipids, etc. were mea- sured in fresh plasma by standard methods. Plas- ma samples for leptin measurement were immedi- ately centrifuged (2,000 rpm for 10 min), decanted and frozen at temperature –70°C. Leptin concentra- tion in plasma samples was quantified using Human Leptin RIA (RadioImmunoAssay) kit from Linco Research, Inc., St. Charles, Missouri, USA. Sensi- tivity of the assay was 0.5 ng/mL. Intra- and inter- assay coefficients of variation were 4.6% and 6.2%, respectively.
Exercise stress testing
Each subject performed a symptom-limited maximal exercise treadmill test according to the modified Bruce protocol. Blood pressure was moni- tored by using mercurial sphygnomanometer and a 12-lead ECG was recorded at rest, every minute during exercise and during recovery, until heart rate (HR) and ECG returned to the baseline values (us- ing the modified Mason-Likar 12-lead system, Mar- quette Case 12; Marquette Electronics, Milwaukee, Wisconsin, USA). All treadmill tests were super- vised by a cardiologist. The main reasons of stop- ping the tests were reaching the age-adjusted limit of HR and/or fatigue. None of the tests were dis- continued because of signs of ischemia in ECG and/
/or angina. The following parameters were analyzed:
duration and distance of exercise stress test, work- load in metabolic equivalents (METs), HR at rest and at peak exercise (max HR).
Exercise training program
Ex group patients underwent a six-week con- trolled, standardized exercise training program on bicycle ergometer, three times a week. Each ses- sion included a ten-minute warm-up, 40 minutes of cycling with telemetry monitoring (the intensity set at 60% at the beginning of the exercise program was progressively increased to 80% of peak HR mea- sured during exercise stress testing), and a ten- minute cool-down. The training was documented by a written protocol.
Cardiac rhythm was continuously monitored on a three-channel telemetry system in all trained pa- tients and in all sessions throughout the study. No patient left the program at any point during the study.
Patients in the control group were advised to walk at least three times per week for 30 minutes during the study period.
Statistical analysis
Statistical analysis was performed using SAS statistical software (Version 9.2, Cary, North Caro- lina, USA). Values are expressed as mean ± stan- dard deviation for normally distributed variables.
Normal distribution was evaluated by the Shapiro- -Wilk test. The difference in mean values was com- pared with Student’s t-test, either the unpaired one to detect differences between groups, or the paired one to detect differences within each group over time.
Comparisons of non-normally distributed data were carried out using the Wilcoxon rank test.
A p value of less than 0.05 was considered statisti- cally significant.
Results Baseline results
No significant differences were found between Ex and control groups regarding age, number of smokers, presence of hypertension, history of myo- cardial infarction or left ventricular ejection fraction (Table 1). There were no significant differences between the groups in terms of baseline metabolic parameters considered or BMI (Table 2). Similar- ly, HR at rest and at peak exercise as well as METs were comparable between the two groups at the beginning of the study (Table 3). Moreover, at the initial evaluation, leptin levels did not differ signif- icantly between the two groups (Table 2).
Final results
Sixty-four patients completed the study. No adverse events occurred in either group during the study period. As shown in Table 2, no significant differences were found between the two groups in
any of the analyzed metabolic parameters. More- over, BMI, WHR and waist circumference were stable and did not change significantly in either study group during the study period. After six weeks, exercise duration and distance improved significantly in both study groups (Table 3). How- ever, in the Ex group only, maximal workload in METs increased significantly (7.7 ± 1.4 vs 8.2 ± Table 1. Study population.
Characteristic Exercise Control P
group group
(n = 32) (n = 32)
Age (years) 54.0 ± 4.8 54.5 ± 5.6 NS CAD (years) 3.9 ± 4.6 2.8 ± 3.7 NS
History MI 20 (62%) 19 (58%) NS
Non-smokers 28 (87%) 27 (83%) NS
Smokers 4 (13%) 5 (17%) NS
Hypertension 25 (78%) 25 (78%) NS Coronary
angiography:
1 vessel 5 (16%) 5 (16%) NS
2 vessels 11 (34%) 7 (22%) NS
3 vessels 16 (50%) 20 (62%) NS Medication:
Beta-blocker 32 (100%) 32 (100%) NS
ACE-I 30 (94%) 30 (94%) NS
AT II blocker 3 (9%) 2 (6%) NS Statins 32 (100%) 32 (100%) NS
Aspirin 31 (98%) 31 (98%) NS
Clopidogrel/ 2 (6%) 2 (6%) NS
/ticlopidine
LVEF (%) 60.0 ± 7.5 56.8 ± 8.9 NS
CAD — coronary artery disease; MI — myocardial infarction; ACE-I
— angiotensin converting enzyme inhibitor; AT II blocker — angio- tensin II receptor blocker; LVEF — left ventricular ejection fraction;
NS — non significant
Table 2. Metabolic parameters at baseline and at the end of the study.
Variables Exercise group (n = 32) Control group (n = 32)
Baseline Final Baseline Final
Body mass index [kg/m²] 27.3 ± 2.8 27.4 ± 2.8 28.0 ± 3.2 28.4 ± 3.6
Waist circumference [cm] 95.8 ± 7.0 96.0 ± 8.4 99.6 ± 7.6 99.8 ± 7.5
Waist-to-hip ratio 1.02 ± 0.05 1.01 ± 0.05 1.03 ± 0.05 1.03 ± 0.06
Total cholesterol [mmol/L] 3.9 ± 0.7 3.8 ± 0.8 4.1 ± 0.6 4.2 ± 1.0
HDL cholesterol [mmol/L] 1.3 ± 0.4 1.3 ± 0.5 1.3 ± 0.4 1.3 ± 0.3
LDL cholesterol [mmol/L] 2.4 ± 0.8 2.3 ± 0.7 2.6 ± 0.8 2.6 ± 0.7
Triglycerides [mmol/L] 1.3 ± 0.6 1.4 ± 0.7 1.4 ± 0.7 1.5 ± 0.9
Fasting glucose [mmol/L] 5.1 ± 0.7 5.1 ± 0.7 5.2 ± 0.7 5.2 ± 0.6
Post-prandial glucose [mmol/L] 5.5 ± 1.5 5.6 ± 1.6 5.7 ± 1.8 5.6 ± 1.5
Leptin [ng/mL] 6.7 ± 3.2 6.9 ± 3.6 8.0 ± 4.0 9.3 ± 5.2*
All results are presented as mean ± SD; *p < 0.05
± 1.4, p < 0.03) compared to the control patients (7.3 ± 1.8 vs 7.7 ± 1.9, p = NS; Table 3).
Although, at the end of the study, leptin levels increased significantly only in the control patients (15% vs 2% in Ex group), there were no signifi- cant statistical differences between the two study groups (Table 2).
Discussion
This preliminary study aimed to investigate the effect of short-term exercise training on plasma leptin concentrations in stable CAD patients with preserved left ventricular function.
We found that our supervised exercise-train- ing program improved physical capacity and did not affect leptin levels. On the contrary, in control pa- tients, home-based activity e.g. walking did not change physical capacity measured in METs and caused an unfavorable increase in leptin levels.
Leptin is secreted by adipose tissue and its concentration in humans is known to correlate with weight, BMI [6] and body fat mass [7–9]. Moreover, leptin is thought to exert many potentially proat- herogenic effects such as induction of endothelial cell dysfunction [10] and platelet aggregation [11], stimulation of inflammatory reactions [4, 5], propa- gation of oxidative stress [12], and proliferation of vascular smooth muscle cells [13].
To date, the influence of exercise training on leptin levels has been examined only in healthy, obese or diabetic patients. The majority of these studies have documented that short-term exercise training does not affect leptin levels.
However, Ishii et al. [14] showed that in type 2 diabetic patients, exercise training reduced plasma leptin levels, which was independent of changes in body fat mass.
Ours was the first study to show the influence of short aerobic training on leptin levels in patients
with CAD. It should be emphasized that BMI, WHR and waist circumference did not change sig- nificantly in either of our study groups. Thus, we can conclude that an increase in plasma leptin con- centration in the control patients was not asso- ciated with changes in weight or waist circumfe- rence. Since a significant increase of physical ca- pacity measured in METs was observed only in the trained patients. We suggest that only a properly applied training program is able to prevent an in- crease in leptin level in optimally treated, clinically stable CAD patients.
Our findings, although promising, require con- firmation on a larger number of patients to deter- mine whether exercise training has a beneficial impact on leptin levels. In addition, the mechanism of favorable influence of exercise training on leptin levels deserves further investigation.
It might be of great importance, because se- veral clinical studies have demonstrated that high leptin levels predicted the development of acute cardiovascular events, restenosis after coronary angioplasty and cerebral stroke, independently of traditional risk factors [2, 15, 16].
Limitations of the study
When interpreting our findings, one should take into account that this was a small, short-du- ration pilot study aimed only at determining whether exercise training had any impact on lep- tin levels. Our study did not assess the percent- age of body fat. However, Flegal et al. [17] showed that it positively correlated with waist circumfer- ence in men, which was measured in our patients.
We did not include women in this study because it is widely recognized that leptin levels are se- veral times higher in women that in men, indepen- dently of fat mass content, suggesting that fe- males have higher leptin levels per unit fat mass [18, 19].
Table 3. Parameters during exercise stress test at baseline and at the end of the study.
Variables Exercise group (n = 32) Control group (n = 32)
Baseline Final Baseline Final
Duration [s] 759.8 ± 96.8 830.1 ± 74.7* 750.5 ± 102.8 781.0 ± 136.5*
Distance [m] 672.7 ± 135.5 778.7 ± 117.8* 644.1 ± 152.3 717.6 ± 164.2*
Metabolic equivalents 7.7 ± 1.4 8.2 ± 1.4* 7.3 ± 1.8 7.7 ± 1.9
Heart rate at rest [bpm] 68.1 ± 11.3 62.9 ± 10.5* 65.1 ± 9.4 64.2 ± 8.2 Max heart rate [bpm] 125.9 ± 15.2 124.8 ± 15.6 121.2 ± 16.7 125.4 ± 15.3
All results are presented as mean ± SD; *p < 0.05
Conclusions
1. A short period of exercise training in CAD pa- tients improved physical capacity, but did not influence BMI, WHR or waist circumference.
2. Exercise training prevented an increase in lep- tin levels during the study period.
Acknowledgements
The authors do not report any conflict of inte- rest regarding this work.
The study was supported by the grant N° 2.11/
/I/07 from the Institute of Cardiology, Warsaw, Po- land.
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